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Nathan Goodyear

Peripheral oxidative stress in relapsing-remitting multiple sclerosis - 0 views

www.sciencedirect.com/...S0009912012000525

MS multiple sclerosis glutathione reduced oxidized perioxidase glutathione-S-transferase glutathione peroxidase GSH GSSG SOD GST 8OHdG 8-hydroxy-2-deoxyguanosine oxidative stress

shared by Nathan Goodyear on 19 Mar 14 - No Cached
  • Nathan Goodyear on 19 Mar 14
     
    Relapsing remitting MS patients found to have in increased 8OHdG, reduced glutathione, reduced glutathione to oxidized glutathione ratio, super oxidized disumutase, glutathione reductase, and global oxidative stress.  In contrast, decreased total antioxidant capacity, oxidized glutathione, glutathione perioxidase, and glutathione transferase were found in relapsing remitting MS patients.
Nathan Goodyear

Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in C... - 0 views

gut.bmj.com/...364.abstract

Calprotectin IBD inflammatory bowel disease inflammation GI gut ulcerative colitis

shared by Nathan Goodyear on 21 May 14 - No Cached
  • Nathan Goodyear on 21 May 14
     
    Fecal Calprotectin found to be useful as monitor for Ulcerative colitis relapse.  This was found more specific for UC than Crohn's disease.  There was a 14 fold higher relapse risk in those with levels > 150.
Nathan Goodyear

Gender and sex hormones in multiple sclerosis pathology and therapy - 0 views

www.ncbi.nlm.nih.gov/...PMC2689399

hormones MS multiple Sclerosis Estriol progesterone

shared by Nathan Goodyear on 11 Jan 17 - No Cached
  • It is now well recognized that the disease manifestation is reduced in pregnant women with relapsing-remitting MS
  • This occurs particularly during the third trimester when levels of estrogens (estradiol and estriol) and progesterone (see Table 2) are elevated up to about 20 times
  • This seems well correlated with a decrease in active white matter lesions detected by MRI
  • ...12 more annotations...
  • This clinical improvement is however followed by temporary rebound exacerbations at post-partum, when the hormone levels decline
  • a shift from Th1 to Th2 immune response, expansion of suppressive regulatory T lymphocytes and decrease in the number of circulating CD16+ natural killer (NK)-cells
  • Th1 lymphocytes secrete proinflammatory cytokines (e.g. IL-2, IFNgamma, lymphotoxin) while Th2 cells secrete anti-inflammatory cytokines (e.g. IL-4, IL-5, IL-10), which favor humoral-mediated responses
  • Th2 cytokines are associated with down-regulation of Th1 cytokines and this Th2 shift is believed to provide protection from allograft rejection during pregnancy as well as from Th1-mediated autoimmune disease
  • it is worth noting that the levels of other hormones with anti-inflammatory activity (1,25-dihydroxy-vitamin D3, norepinephrine, cortisol) also increase by 2 to 4 times during late pregnancy
  • 1,25-dihydroxy vitamin D3 induces regulatory T-cell function important for development of self-tolerance
  • breast-feeding does not alter the relapse rate in women with MS
  • Leptin is a pleiotropic hormone produced primarily by adipocytes but also by T lymphocytes and neurons
  • Several lines of evidence indicate that leptin contributes to EAE/MS pathogenesis, influencing its onset and clinical severity, by acting as a proinflammatory cytokine which promotes regulatory T cell (Treg) anergy and hyporesponsiveness, resulting in increased Th1 (TNFalpha, INFgamma) and reduced Th2 (IL-4) cytokine production
  • circulating leptin levels are increased in relapsing-remitting MS patients (men and women analyzed together) while the CD4+CD25+Treg population decreases
  • As the leptin plasma concentrations are proportional to the amount of fat tissue, obese/overweight individuals produce higher levels of leptin
  • Nielsen et al found that estradiol and progesterone exert neuroprotection against glutamate neurotoxicity, while MPA antagonizes the neuroprotective effect of estradiol and exacerbated neuron death induced by glutamate excitotoxicity
  • Nathan Goodyear on 11 Jan 17
     
    very good review of the differences in MS and hormones between the sexes.
Nathan Goodyear

Intravenous Vitamin C Administration Improved Blood Cell Counts and Health-Related Qual... - 0 views

www.ncbi.nlm.nih.gov/...PMC6070822

acute myeloid leukemia IV vitamin C vitamin C AML

shared by Nathan Goodyear on 29 May 20 - No Cached
  • Nathan Goodyear on 29 May 20
     
    Case study of IV vitamin C twice weekly for treatment of relapse AML.
Nathan Goodyear

https://www.jstage.jst.go.jp/article/jmi/61/1.2/61_35/_pdf - 0 views

www.jstage.jst.go.jp/..._pdf

prostate cancer PSA Testosterone men male hormone hormones androgen deprivation therapy

shared by Nathan Goodyear on 09 Apr 14 - No Cached
  • Nathan Goodyear on 09 Apr 14
     
    study looked at androgen deprivation therapy in non-metastatic prostate cancer.  This study found that the elimination of ADR post 5 years was associated with low recurrence.  Relapse of increased PSA was associated with increasing Testosterone off of ADR.  This study did not look at estrogens or androgen metabolites.  Too short sided in its design.
Nathan Goodyear

Estrogen Receptor β Expression Is Associated with Tamoxifen Response in ERα-N... - 0 views

clincancerres.aacrjournals.org/...1987.long

ER beta ER-beta estrogen receptors breast cancer tamoxifen estrogen receptor estrogen receptor women hormone hormones

shared by Nathan Goodyear on 08 Oct 14 - No Cached
  • Nathan Goodyear on 08 Oct 14
     
    Increased survival in those with ER beta + and ER alpha -.  Early relapse was associated with lack of ER beta expression.  ER beta is transcribed from a different genomic location than ER alpha.  
Nathan Goodyear

Mucosal Immunology - Molecular signatures of a disturbed nasal barrier function in the ... - 0 views

www.nature.com/...mi20119a.html

S aureus Staphylococcus aureus autoimmune disease disease autoimmune Wegener's granulomatosis WG Wegener's vasculitis

shared by Nathan Goodyear on 15 Sep 15 - No Cached
  • Nathan Goodyear on 15 Sep 15
     
    nasal mucos colonization of S aureus found to be associated with Wegener's vasculitis as well as relapse.
Nathan Goodyear

Effects of a restricted elimination diet on the behaviour of children with attention-de... - 0 views

www.thelancet.com/...abstract

attention-deficit disorder hyperactivity ADHD

shared by Nathan Goodyear on 28 Jun 11 - No Cached
  • Nathan Goodyear on 28 Jun 11
     
    elimination diet improves ADHD symptoms based on IgG results; though relapse occurred independent of the IgG blood levels, so they discourage the use of IgG.  Makes no sense.
Nathan Goodyear

Treatment of multiple sclerosis with the pregnanc... [Ann Neurol. 2002] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...12325070

MS multiple sclerosis Estriol hormone hormones women multiple sclerosis

shared by Nathan Goodyear on 07 Jan 14 - No Cached
  • Nathan Goodyear on 07 Jan 14
     
    Estriol, the dominant estrogen in pregnancy shown to decrease MS symptoms.  When Estriol was stopped, MS lesions relapsed.  Estriol binds to ERbeta at a rate of 5:1 compared to ER alpha.
Nathan Goodyear

Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in t... - 0 views

www.jneurosci.org/...12312.long

Testosterone polyneuropathy MS multiple Sclerosis Estriol hormones autoimmune disease

shared by Nathan Goodyear on 17 Mar 15 - No Cached
  • direct androgen receptor activation is not a mutually exclusive requirement of testosterone-mediated neuroprotection.
  • Testosterone treatment after EAE induction restores synaptic transmission and corresponding synaptic protein levels within the hippocampus during EAE
  • A growing body of evidence suggests that testosterone enhances hippocampal synaptogenesis
  • ...7 more annotations...
  • This study demonstrates that testosterone treatment either before or after EAE disease induction partially restores deficits in synaptic transmission, preserves presynaptic and postsynaptic integrity, and prevents hippocampal pathology.
  • treatment with a pregnancy estrogen, estriol, can prevent deficits in excitatory synaptic transmission in the hippocampus during EAE
  • testosterone is important to the maintenance of normal synaptic spine density in the hippocampus
  • estriol treatment was also capable of preserving levels of synaptic proteins that are known to orchestrate functional synaptic transmission within the hippocampus.
  • Estriol is a therapeutic candidate in MS because it has widespread effects on the immune system and the CNS
  • MS patients have significantly decreased relapse rates during the third trimester of pregnancy, when estriol levels are most elevated, and relapse rates rebound during the postpartum period coinciding with an abrupt decline in serum estriol levels
  • In nonpregnant MS patients, estriol treatment has been shown to significantly reduce gadolinium-enhancing lesion number and volumes measured by MRI
  • Nathan Goodyear on 17 Mar 15
     
    Testosterone restores/preserves nerve synapsis within the hippocampus in autoimmune demyelinating disease.  Testosterone appears to have neuroprotection.  The authors conclude that the majority of the protective effect was through aromatase activity.
Nathan Goodyear

The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of... - 0 views

www.ncbi.nlm.nih.gov/...PMC2011337

thymidine kinase 1 TK-1cancer

shared by Nathan Goodyear on 11 Feb 15 - No Cached
  • Nathan Goodyear on 11 Feb 15
     
    Thymidine kinase 1 useful as a prognostic biomarker and to monitor therapy efficacy. TK-1 levels were very low in those without cancer. Higher TK-1 levels pretreatment were associated with poor prognosis and poor survival. TK-1 "increases with progress of the disease, decreases during successful therapy, and finally increases during relapse.
Nathan Goodyear

Intravenous Vitamin C and Cancer: A Syste... [Integr Cancer Ther. 2014] - PubMed - NCBI - 1 views

www.ncbi.nlm.nih.gov/...24867961

IV vitamin C intravenous vitamin C vitamin C IV intravenous cancer IVC ascorbic acid

shared by Nathan Goodyear on 27 Aug 14 - No Cached
  • Nathan Goodyear on 27 Aug 14
     
    So help me out here:  If IV vitamin C has been shown to prolong time to cancer relapse, aid in reducing tumor size, improve survival with chemotherapy, improve quality of life, improve physical function, reduce chemo side effects, improve energy, reduce nausea, aid insomnia, reduce constipation, and improve depression in cancer patient--then why does the author say that IV vitamin C is contentious?  Add that IV vitamin C has not been implicated in any deaths in cancer therapy.  Contrast that with chemotherapy.  Why again is this contentious?  Whom is best served by this being contentious?
Nathan Goodyear

The 4-Pregnene and 5α-Pregnane Progesterone Metabolites Formed in Nontumorous... - 0 views

cancerres.aacrjournals.org/...936.full

progesterone metabolism cancer risk 4-pregnene 5alpha-pregnane

shared by Nathan Goodyear on 17 Feb 12 - No Cached
  • We report here the first evidence that tumorous breast tissue exhibits elevated 5α-reductase activity, which promotes significant increases in 5α-pregnanes, especially 5αP,4 whereas the normal (nontumorous) breast tissue produces more 4-pregnenes, especially 3αHP
  • 3αHP and other 4-pregnenes inhibit, whereas 5αP and other 5α-pregnanes stimulate, breast cell proliferation and detachment
  • it is evident that breast tissue can convert progesterone into two classes of metabolites: the δ-4-pregnenes (which retain the C4–5 double bond), and the 5α-reduced 21-carbon steroids (5α-pregnanes)
  • ...12 more annotations...
  • irreversible action of 5α-reductase
  • in normal (nontumorous) breast tissue, the 4-pregnene metabolites of progesterone greatly exceeded the 5α-pregnanes, whereas in tumorous tissue, 5α-pregnanes exceeded 4-pregnenes.
  • These differences in 5α-pregnane and 4-pregnene amounts were largely attributable to differences in 5αP and 3αHP production in tumorous and nontumorous tissues
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
  • These findings suggest greatly elevated 5α-reductase activity in tumorous, as compared with nontumorous, breast tissue.
  • progesterone metabolites that retain the C-4 double bond (i.e., the 4-pregnenes) exert an antiproliferative effect in the three cell lines that were tested, whereas the 5α-pregnanes stimulate breast cell line proliferation.
  • the degree of mitogenicity would be determined by the ratio of 5α-pregnanes:4-pregnenes. Tissues with a high 4-pregnene:5α-pregnane ratio would maintain a higher degree of normalcy, whereas those with a high 5α-pregnane:4-pregnene ratio would tend toward tumorigenicity
  • The observations that progesterone metabolites affect both ER-positive and ER-negative cells as well as tumorigenic (MCF-7) and nontumorigenic (MCF-10A) cells strengthen the argument that these factors may be endocrinologically relevant for all forms of breast cancer.
  • progesterone metabolites as the active endocrine/paracrine/autocrine factors
  • Estrogen-based therapies elicit responses in only one-third of all breast cancer patients, and most of these show relapse.
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
    • Nathan Goodyear
      Nathan Goodyear on 27 Jan 14
       
      Interesting that the effect of progesterone metabolites were found to be independent from ER status, age, and pre/post menopause
  • Nathan Goodyear on 17 Feb 12
     
    Different progesterone metabolites shown to have different tumor effects.  Implications are that, just as estrogen metabolism effects cancer risk, so does progesterone metabolism.
Nathan Goodyear

The molecular basis of neurodegeneration in multiple sclerosis - 0 views

www.sciencedirect.com/...S001457931100593X

MS multiple sclerosis neurodegenerative disease CNS brain inflammation

shared by Nathan Goodyear on 19 Mar 14 - No Cached
  • Inflammation is the most predominant feature during the early (relaping) phases of the disease and declines with aging of the patients and disease duration
  • in the process of oligodendrocyte destruction and demyelination in MS lesions iron is liberated from its intracellular ferritin bound stores into the extracellular space, where it is taken up by microglia and macrophages and again stored together with ferritin. When this happens in MS lesions in an environment, where free radicals are produced by oxidative burst, iron can be liberated from ferritin and transformed into reactive Fe++[114], which reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals [36] and thus amplifies oxidative damage and associated cellular injury
  • anti-inflammatory or immunomodulatory treatments are effective in the relapsing stage, but the benefit is lost when the patients have entered the progressive phase
  • ...1 more annotation...
  • Inflammation will remain a key target, since the data suggest that microglia activation and oxidative burst is driven by inflammation throughout all stages of the disease.
  • Nathan Goodyear on 19 Mar 14
     
    Very nice review of the neurodegenerative process in MS.  
Nathan Goodyear

Oncotarget | Vitamin C and Doxycycline: A synthetic lethal combination therapy targetin... - 0 views

www.impactjournals.com/...index.php

cancer doxycycline IV vitamin C vitamin C

shared by Nathan Goodyear on 14 Jun 17 - No Cached
  • These eight distinct cancer types included: DCIS, breast (ER(+) and ER(-)), ovarian, prostate, lung, and pancreatic carcinomas, as well as melanoma and glioblastoma. Doxycycline was also effective in halting the propagation of primary cultures of CSCs from breast cancer patients, with advanced metastatic disease (isolated from ascites fluid and/or pleural effusions)
  • Doxycycline behaves as a strong radio-sensitizer, successfully overcoming radio-resistance in breast CSCs
  • cancer cells can indeed escape the effects of Doxycycline, by reverting to a purely glycolytic phenotype. Fortunately, the metabolic inflexibility conferred by this escape mechanism allows Doxycycline-resistant (DoxyR) CSCs to be more effectively targeted with many other metabolic inhibitors, including Vitamin C, which functionally blocks aerobic glycolysis
  • ...36 more annotations...
  • Vitamin C inhibits GAPDH (a glycolytic enzyme) and depletes the cellular pool of glutathione, resulting in high ROS production and oxidative stress
  • DoxyR CSCs are between 4- to 10-fold more susceptible to the effects of Vitamin C
  • Doxycycline and Vitamin C may represent a new synthetic lethal drug combination for eradicating CSCs, by ultimately targeting both mitochondrial and glycolytic metabolism
  • inhibiting their propagation in the range of 100 to 250 µM
  • metabolic flexibility in cancer cells allows them to escape therapeutic eradication, leading to chemo- and radio-resistance
  • used doxycycline to pharmacologically induce metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis
  • This treatment resulted in a purely glycolytic population of surviving cancer cells
  • DoxyR cells are mainly glycolytic
  • MCF7 cells survive and develop Doxycycline-resistance, by adopting a purely glycolytic phenotype
  • Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance
  • the conserved evolutionary similarities between aerobic bacteria and mitochondria, certain classes of antibiotics inhibit mitochondrial protein translation, as an off-target side-effect
  • Vitamin C was more potent than 2-DG; it inhibited DoxyR CSC propagation by > 90% at 250 µM and 100% at 500 µM
  • IC-50
  • DoxyR CSCs are between 4- to 10-fold more sensitive to Vitamin C than control MCF7 CSCs
  • Berberine, which is a naturally occurring antibiotic that also behaves as an OXPHOS inhibitor
  • treatment with Berberine effectively inhibited the propagation of the DoxyR CSCs by > 50% at 1 µM and > 80% at 10 µM.
  • Doxycycline, a clinically approved antibiotic, induces metabolic stress in cancer cells. This allows the remaining cancer cells to be synchronized towards a purely glycolytic phenotype, driving a form of metabolic inflexibility
  • Doxycycline-driven aerobic glycolysis
  • new synthetic lethal strategy for eradicating CSCs, by employing i) Doxycycline (to target mitochondria) and ii) Vitamin C (to target glycolysis)
  • Doxycycline inhibits mitochondrial biogenesis and OXPHOS,
  • hibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH
  • CSCs act as the main promoter of tumor recurrence and patient relapse
  • a metabolic shift from oxidative to glycolytic metabolism represents an escape mechanism for breast cancer cells chronically-treated with a mitochondrial stressor like Doxycycline, as mitochondrial dys-function leads to a stronger dependence on glucose
  • Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models
  • many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool
  • here we show that DoxyR CSCs are more vulnerable to the inhibitory effects of Vitamin C, at 4- to 10-fold lower concentrations, between 100 to 250 μM
  • concurrent use of Vitamin C, with standard chemotherapy, reduces tumor recurrence and patient mortality
  • after oral administration, Vitamin C plasma levels reach concentrations of ~70-220 μM
  • intravenous administration results in 30- to 70- fold higher plasma concentrations of Vitamin C
  • pro-oxidant activity results from Vitamin C’s action on metal ions, which generates free radicals and hydrogen peroxide, and is associated with cell toxicity
  • it has been shown that high-dose Vitamin C is more cytotoxic to cancer cells than to normal cells
  • This selectivity appears to be due to the higher catalase content observed in normal cells (~10-100 fold greater), as compared to tumor cells. Hence, Vitamin C may be regarded as a safe agent that selectively targets cancer cells
  • the concurrent use of Doxycycline and Vitamin C, in the context of this infectious disease, appeared to be highly synergistic in patients
  • Goc et al., 2016, showed that Doxycycline is synergistic in vitro with certain phytochemicals and micronutrients, including Vitamin C, in the in vitro killing of the vegetative spirochete form of Borrelia spp., the causative agent underlying Lyme disease
  • Doxycycline, an FDA-approved antibiotic, behaves as an inhibitor of mitochondrial protein translation
  • CSCs successfully escape from the anti-mitochondrial effects of Doxycycline, by assuming a purely glycolytic phenotype. Therefore, DoxyR CSCs are then more susceptible to other metabolic perturbations, because of their metabolic inflexibility
  • Nathan Goodyear on 14 Jun 17
     
    Not especially new, but IV vitamin C + daily doxycycline found to kill cancer stem cells.
Nathan Goodyear

Elevated Troponin and Jarisch-Herxheimer Reaction in Tick-Borne Relapsing Fever: A Case... - 0 views

www.hindawi.com/...950314

Jarish-Herxheimer borrelia Lyme disease inflammation

shared by Nathan Goodyear on 23 Jan 18 - No Cached
  • Nathan Goodyear on 23 Jan 18
     
    case-study of a Jarisch-Herxheimer reaction with a patient with Borrelia (Lyme)
Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views

www.nature.com/...s41698-017-0044-8

cancer cancer stem cells liver cancer vitamin C IV vitamin C oncology

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
  • ...41 more annotations...
  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      positive results despite a low dose used.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
Nathan Goodyear

Improved leukemia-free survival after postconsolidation immunotherapy with histamine di... - 0 views

www.bloodjournal.org/...88

AML acute myeloid leukemia leukemia IL-2 histamine

shared by Nathan Goodyear on 12 May 18 - No Cached
  • several independent lines of evidence suggest that cytotoxic effector cells such as T cells and natural killer (NK) cells participate in protecting patients with AML against relapse
  • A plethora of mechanisms have been proposed to account for the dysfunctional antileukemic lymphocytes in AML, including the production of T-cell- and NK-cell-inhibitory factors by AML blasts,48 a deficient expression of NK-cell receptors on leukemic cells,49 inhibition of antileukemic lymphocytes by mononuclear phagocytes,4 and an impaired stimulatory interaction between the CD28 antigen expressed by T cells and contact antigens on AML blasts
  • This trial met the primary endpoint and thus showed a significantly improved LFS for patients receiving HDC/IL-2 as compared with the current standard of care
  • ...2 more annotations...
  • T cells and NK cells with antileukemic activity can be recovered from most patients with AML in remission not receiving a transplant,
  • The present study evaluated an approach to immunotherapy in AML in which IL-2 is supplemented with histamine dihydrochloride (HDC) to enhance the function of cytotoxic antileukemic lymphocytes
  • Nathan Goodyear on 12 May 18
     
    IL-2 plus histamine in patients with AML complete remission improves leukemia free survival.
Nathan Goodyear

Interleukin‐2 enhances the natural killer cell response to Herceptin‐coated H... - 1 views

onlinelibrary.wiley.com/...%3AAID-IMMU3016%3E3.0.CO%3B2-J

IL-2 breast cancer cancer NK cells HER-2 immunotherapy

shared by Nathan Goodyear on 18 Jun 18 - No Cached
  • administration of low‐dose IL‐2 results in expansion of a CD3– / CD56+ NK cell population in patients with advanced cancer
  • approximately 20 % will overexpress theHer2 / neu proto‐oncogene
  • In breast cancer, Her2 / neu overexpression is associated with a worse histologicalgrade, decreased relapse‐free and overall survival periods, and altered sensitivity to chemotherapeutic regimens
  • ...17 more annotations...
  • NK cells are large granular lymphocytes that comprise approximately 10 % of circulating lymphocytes
  • all human NK cells express the CD56 antigen
  • treatment with various concentrations of IL‐2 in vivo may induce distinct functions within the NK cell compartment and, therefore, may have profound effects on NK cell‐mediated cytotoxicity
  • CD56bright
  • CD56dim
  • We show here that ADCC conducted by NK cells in vitro is enhanced by IL‐2 activation and is critically dependent on interactions between FcγRIII on NK cells and Herceptin‐coated tumor targets
  • administration of low‐dose IL‐2 to patients results in the marked expansion of a CD56+ population of immune effectors with the ability to lyse antibody‐coated cancer targets
  • NK cells represented only 7 % of lymphocytes prior to therapy but comprised over 50 % of the population after 10 weeks of low‐dose IL‐2
  • These data suggest that the enhanced ADCC seen following the expansion of NK cells with low‐dose IL‐2 is likely due to an increase in the overall number of NK cells
  • co‐administration of IL‐2 with rhu4D5 mAb will enhance activation of NK cell effector functions
  • Stimulation of NK cells with IL‐2 resulted in a significant increase in the lysis of rhu4D5‐coated targets
  • We have shown that costimulation with IL‐2 plus rhu4D5 results in significant production of IFN‐γ by NK cells with concomitant up‐regulation of cell‐surface activation and adhesion molecules
  • It has been previously demonstrated that continuous low‐dose IL‐2 can expand a CD56+ lymphocyte population, and we have now shown that this cell population is a potent mediator of ADCC against rhu4D5 mAb‐coated Her2 / neu+ targets
  • These results suggest that administration of low‐dose IL‐2 can be used to expand NK cell numbers, while higher doses may be used to enhance their cytolytic capacity in the setting of mAb therapy
  • we have demonstrated that NK cell lysis of Her2 / neu+ breast cancer cell lines in the presence of rhu4D5 mAb is markedly enhanced following stimulation with IL‐2
  • we have presented evidence that administration of low‐dose IL‐2 in vivo results in the expansion of a potent NK cell effector population
  • Our experiments suggest that NK cells costimulated with IL‐2 and immobilized IgG can secrete potent immunomodulatory cytokines which may serve to potentiate the anti‐tumor immune response.
  • Nathan Goodyear on 18 Jun 18
     
    low dose IL-2 found to expand NK levels in conjuction in with herceptin in HER-2 positive breast cancer cell lines.
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